1. Technical Field
The present invention relates generally to antigen-binding protein molecules involved in immune function. More particularly, the present invention relates to recombinant antibodies, chimeric antigen receptors and fragments thereof with specificity for an HLA-restricted peptide, where the peptide is derived from a cellular or viral protein of interest.
2. Background Information
Advances in adoptive T cell immunotherapy have led to several promising options for cancer patients in the past decade. T-cell based immunotherapy for cancer stemmed from studies which showed a correlation of increased numbers of tumor infiltrating lymphocytes (TILs) in surgical specimens and patient outcome. It is generally believed that this infiltration of TILs represents activation of an anti-tumor mechanism and that the infiltration was mediated through the expression of tumor associated antigens in the context of MHC. These findings eventually led researchers to try and take advantage of antigen-specific T cells for the treatment of cancer.
For induction of cytotoxic T-cell (CTL) responses, intracellular proteins are usually degraded by the proteasome or endo/lysosomes, and the resulting peptide fragments bind to MHC class I or II molecules. These peptide-MHC complexes are displayed at the cell surface where they provide targets for T cell recognition via a peptide-MHC (pMHC)-T cell receptor (TCR) interaction. Vaccinations with peptides derived from cellular and viral protein can induce HLA-A0201-restricted cytotoxic CD8 T cells, which are capable of killing tumor cells or virally-infected cells.
Antibodies are increasingly being used as therapeutic agents to fight cancer, autoimmune disease and infection. Therapeutic antibodies have been exploited based on their multiple mechanisms of action, which include the following: 1) naked antibodies killing tumor cells directly by ADCC or CDC (e.g. trastuzumab), 2) blocking or stimulating a cell membrane molecule to induce cell death (e.g. cetuximab), 3) neutralizing a secreted moiety (e.g. bevacizumab), 4) killing via an attached moiety such as a drug, toxin, radioisotope and 5) modulating the immune system via T cell effector functions.
In almost all cases, to generate a therapeutic benefit, antibodies have to possess critical properties including high affinity for their targeted antigen, minimal acute and long-term side effects, and in specific applications, high affinity for human Fc receptors (4). In addition, the targeted antigen has to be expressed at high levels on tumors but not on normal tissues (specificity or selectivity), consistently expressed in the specific tumor among patients and within patients (low heterogeneity), and should either be essential for the survival of the cancer cell or unlikely to be down regulated.
To achieve these attributes, researchers can now reengineer existing antibodies to make them less immunogenic, modifying both protein and carbohydrate residues in the Fc regions to enhance ADCC and CDC, shrinking their sizes for potentially better tumor penetration, mutating the variable regions to improve affinity, increasing avidity by changing antibody valency, and constructing novel antibody-fusion proteins such as those for multi-step targeting (5) and for redirecting immune cells by way of a chimeric antigen receptor (CAR). Furthermore, researchers continue to define the structural attributes and the host characteristics responsible for success among currently approved antibodies (6).
With the objective of eliminating or neutralizing the pathogenic agent or disease target, including bacterial, viral or tumor targets, antigen-specific, antibody-based treatments are particularly attractive because of the antibody's exquisite specificity.